Age related changes in pharmacokinetics of tricyclic antidepressant drugs such as nortriptyline (NT) result in increased concentrations of biologically active metabolites at a given dose. 10-hydroxynortriptyline (10-0H-NT) is the major active metabolite of NT. Relative concentrations of plasma 10-OH-NT vary greatly between individuals; this is superimposed on the variability of NT concentrations themselves. In young adult depressives treated with NT, correlations between therapeutic response and plasma concentrations may be stronger when 10-OH-NT is taken into account. Relationships between plasma tricyclic antidepressant concentrations and therapeutic or toxic effects have not been well defined in the elderly. 10-OH-NT concentrations are especially important when concentration-effect relationships are assessed in elderly depressives treated with NT. Young adult (18-40 years) and elderly (greater than or equal to 60 years) inpatients with primary unipolar major depression, endogenous subtype, will be studied before and during treatment with NT. Multiple measures of depressive state severity will be recorded after a psychotropic drug washout period and again weekly for four weeks during treatment with NT at a final dose of 75 mg. A side effects scale, lying, sitting, and standing blood pressure, pulse, the electrocardiogram and Holter recording of cardiac rhythm will be monitored. Plasma NT and unconjugated 10-OH-NT concentrations will be measured weekly. Creatinine clearance and urinary 10-OH-NT (conjugated and unconjugated) will also be determined. It is expected that plasma 10-OH-NT concentrations will be higher in the elderly depressives and that they will be inversely related to creatinine clearance and to metabolic clearance of NT by hydroxylation calculated from urinary 10-OH-NT; that NT plasma concentrations will not differ between groups; that toxic effects will be greater in the elderly; that in both groups the relationship between therapeutic and toxic effects and combined NT and 10-OH-NT measures will be stronger than when considering NT alone; that in patients with low plasma NT, responders will more often be elderly and have high plasma 10-OH-NT; and that in patients with moderate plasma NT, nonresponders will more often be elderly and have high plasma 10-OH-NT.